Neural stem/progenitor cells play critical roles during neural development. They serve as the source of all neurons and glia and contribute to the histogenetic processes of nervous system formation. Elucidating the molecular mechanisms governing neural progenitor cell properties and functions is critical to understand not only neural development but also human diseases caused by neural progenitor dysregulation and malfunction. The objective of this application is to investigate the function of a novel signaling pathway, the Hippo pathway, during mammalian brain development. By regulating the activity of the transcriptional coactivators YAP and its paralog TAZ, the Hippo pathway controls the development, homeostasis, and/or tumorigenesis of several mammalian organs. However, its role during mammalian brain development is largely unknown. Our laboratory recently showed that aberrant YAP activation causes overexpansion of the neural progenitor population and that the neurofibromatosis type-2 (NF2) tumor suppressor Merlin is a physiological inhibitor of YAP/TAZ during brain development. Moreover, we discovered a novel function of Merlin and YAP in regulating the formation of the corpus callosum, the largest commissural connection between the cerebral hemispheres. The overall goal of this proposal is to elucidate the molecular mechanism by which Merlin and YAP/TAZ regulate brain development. Specifically, the proposed study will: (1) determine the biochemical mechanism by which Merlin regulates YAP, (2) determine the molecular mechanism through which the Merlin-YAP cascade regulates corpus callosum formation, and (3) define the transcriptional program through which YAP/TAZ regulate neural progenitor properties. The proposed study is expected to define the function of YAP/TAZ during brain development and expand our knowledge on mechanisms regulating neural progenitor behaviors. It will also elucidate the physiological function and mechanism of action of the NF2/Merlin tumor suppressor and provide insight into how NF2 mutations in humans cause or contribute to tumorigenesis. Lastly, it will uncover a novel signaling cascade that regulates axon guidance and provide new insight into the mechanisms underlying callosal malformations, which are among the most common brain anomalies found at birth.